In man general anesthetic agents depress responsiveness of blood vessels to adrenergic stimuli. Certain intravenous, and local anesthetic agents alter the uptake and retention of the neurotransmitter norepinephrine(NE) at postganglionic terminals in blood vessel wall. The overall aim of the proposal is one, to determine the action of halothane and morphine on exocytotic release mechanism in blood vessels, and two, to determine the action of anesthetic agents on neurotransmitter storage vesicles from rat brain. In the studies performed to date it has been found that morphine causes a dose-dependent inhibition of the release of NE from nerve terminals in canine saphenous veins. This inhibition of NE release is not blocked by the morphine antagonist naloxone indicating that the action of morphine is not mediated via an opiate receptor sensitive to nalone. It has also been found that the action of morphine on NE release can be modulated by presynaptic receptor antagonists phenoxybenzamine, and phentolamine, and by the presynaptic agonist - clonidine. This information is useful to anesthesiologists in guiding their choice of vasoconstrictor agents to counteract the depressant action of morphine. The second part of this study is to examine the action of anesthetic agents vesicular release and uptake of NE. Vesicular uptake has as its main function the maintainance of transmitter stores. The cation of anesthetic agents on vesicular storage of NE is clinically relevant because patients treated with reserpine and other drugs which depletes vesicular stores have different anesthetic requirements. Storage vesicles isolated from rat brains display an in vitro NE uptake mechanism with properties that are kinetically and pharmacologically similar to peripheral neurons. Studies planned for the coming year include isolation of cerebral vesicles and determination of the action of anesthetic agents on vesicular release and uptake of 3H-NE.